Uric Acid and Hypertension: An Update With Recommendations

Abstract

The association between increased serum urate and hypertension has been a subject of intense controversy. Extracellular uric acid drives uric acid deposition in gout, kidney stones, and possibly vascular calcification. Mendelian randomization studies, however, indicate that serum urate is likely not the causal factor in hypertension although it does increase the risk for sudden cardiac death and diabetic vascular disease. Nevertheless, experimental evidence strongly suggests that an increase in intracellular urate is a key factor in the pathogenesis of primary hypertension. Pilot clinical trials show beneficial effect of lowering serum urate in hyperuricemic individuals who are young, hypertensive, and have preserved kidney function. Some evidence suggest that activation of the renin-angiotensin system (RAS) occurs in hyperuricemia and blocking the RAS may mimic the effects of xanthine oxidase inhibitors. A reduction in intracellular urate may be achieved by lowering serum urate concentration or by suppressing intracellular urate production with dietary measures that include reducing sugar, fructose, and salt intake. We suggest that these elements in the western diet may play a major role in the pathogenesis of primary hypertension. Studies are necessary to better define the interrelation between uric acid concentrations inside and outside the cell. In addition, large-scale clinical trials are needed to determine if extracellular and intracellular urate reduction can provide benefit hypertension and cardiometabolic disease.

Keywords: blood pressure; fructose; hypertension; renin–angiotensin system; uric acid; xanthine oxidase.

Figure 1.

Generation of uric acid, a purine endproduct. Uric acid can be generated from precursors, primarily umami-based foods, as well as from ATP degradation, such as occurs with fructose-based sugars, ischemia, and alcohol, or from cell turnover and injury with release of RNA and DNA. The endogenous production of fructose can occur from high glycemic and high salt diets that activate aldose reductase.

Figure 2.

Potential mechanism of uric acid induced hypertension. Uric acid induces oxidative stress, a decrease in endothelial nitric oxide availability, and activation of both plasma renin activity and intrakidney angiotensin activity, leading to kidney vasoconstriction, ischemia, and oxidative stress in the kidney. This triggers activation of the immune system that causes persistent kidney vasoconstriction and salt-sensitive hypertension.

Figure 3.

Intracellular mechanisms of uric acid induced inflammation. Uric acid can be produced inside the cell by activation of xanthine oxidoreductase or by uptake via specific urate transporters. Once uric acid levels increase, there is activation of both mitogen activated protein kinases (MAPK) as well as stimulation of NADPH oxidase that triggers mitochondrial and cytoplasmic oxidative stress. This is associated with activation of inflammatory pathways (including NFκB activation, inflammasome activation, release of growth factors and heat shock proteins) as well as a down regulation of energy production by the mitochondria with a shift toward glycolysis.